An aspergilloma is a fungus ball or mycetoma composed of Aspergillus hyphae along with cellular debris and mucus. It is a noninvasive type of chronic pulmonary aspergillosis. Aspergillus species colonize the preexisting cavity in the lung parenchyma and form a fungus cavity. This activity describes the presentation and management of aspergilloma and highlights the role of the interprofessional team in its management.
Inert saprophytic colonization of preexisting cavitary spaces in pulmonary parenchyma, its presentation, as well as complications thereof, are referred to as aspergilloma. It falls within the broader class of chronic pulmonary aspergillosis. A cavitary space with well-defined walls sequesters the fungal spores from both mechanical clearance, as well as immune eradication.
Description of cavitary aspergillus disease dates back to John Hughes Bennett in 1842, whose description of the soft tuberculous matter in multiple varied-sized cavities in the lung closely resembles aspergillus disease. Deve in 1938 first formally described an aspergilloma and named it “mega mycetoma.”[rx] Subsequently, Hinson, and colleagues defined aspergilloma in its currently understood version as a saprophytic infection of preexisting lung cavities.[rx]
Belcher and Plummer first formulated the classification of aspergilloma in 1960.[rx] If the surrounding lung parenchyma appeared normal and the cavity containing the aspergillus nidus was entirely lined by ciliated epithelium, it was termed a simple aspergilloma.
On the other hand, a complex aspergilloma is one lined by extensively damaged surrounding lung parenchyma with epithelial distortion or destruction and fibrosis. The Wall thickness of a complex aspergilloma is defined to be more than 0.3 cm.
Causes
Aspergillus species are ubiquitous saprophytes in the environment. Pulmonary disease is caused mainly by the species Aspergillus fumigatus.
Risk factors for Aspergillus mediated lung disease, including aspergilloma, are:
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Pulmonary tuberculosis
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Cystic fibrosis
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Chronic bronchiectasis
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Pneumoconiosis
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Post infarct pulmonary cavity
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Post radiation pulmonary cavity
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Sarcoidosis
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Bronchial cysts and bullae
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Chronic lung abscess
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Lung malignancy
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Ankylosing spondylitis
Chronic Debilitating Condition (Impaired local bronchopulmonary defense)
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Malnutrition
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COPD
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Chronic liver disease
Immunosuppression
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Post-transplant
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Stem cell transplant
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Chemotherapy
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Neutropenia
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Prolonged corticosteroid use
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HIV
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Primary immunodeficiency syndromes
Symptoms
People with aspergillomata typically remain asymptomatic until the condition is fairly advanced; in some cases even for decades. Thus, the most common symptom of associated with aspergillomata is coughing up blood (hemoptysis). This may result in life-threatening hemorrhage, though the amount of blood lost is usually inconsequential.
- Coughing up blood, which can be a life-threatening sign
- Fatigue
- Fever
- Unintentional weight loss
Aspergillomata can also form in other organs. They can form abscesses in solid organs such as the brain or kidney, usually in people who are immunocompromised. They can also develop within body cavities such as the sphenoid or paranasal sinuses,[2] the ear canal, and rarely on surfaces such as heart valves.
Diagnosis
Aspergillus is a saprophytic filamentous fungus that thrives in a moist environment in soil, plants, and decaying vegetables. However, the conditions that favor dispersion of spores are dry and dusty surroundings, hay barns, compost sites, etc. Aspergillus fumigatus is the most prevalent human pathogen, although Aspergillus niger, A. flavus, and A. oxyzae are also reported to cause human disease.
The organism is characterized by 4 to 12 mm long septate hyphae with dichotomous branching, and with long conidiophores carrying numerous spores on their tips.
In a histologic specimen, aspergilloma appears as a soft mesh of inflamed, bloated, septate hyphae, fibrin, blood clots, cellular debris, and mucous residues. The central core is often necrotic. Although the lining of a simple aspergilloma could be ciliated epithelium, the epithelial lining is more often pseudostratified columnar or metaplastic squamous epithelium. Depending upon the severity of inflammation and the time course of progression, the walls can have evidence of chronic granulomatous inflammation, lymphoid follicles, endarteritis, and even ulceration and fibrosis.
History and Physical
There is a generalized understanding of predisposition among patients to specific forms of the aspergillus-mediated disease. Individuals with atopy or predisposition to hypersensitivity are more prone to have obstructive bronchopulmonary aspergillosis. Immunocompromised patients more often are the ones to get invasive aspergillus infections, while myeloma is more common in immunocompetent patients with preexisting lung disease. However, the overlap between these predisposition categories exists. Patients with myeloma can develop a hypersensitivity response akin to allergic bronchopulmonary aspergillosis (ABPA).[rx] A chronic mycetoma that is unchanged over months to years can also suddenly metamorphose into a rapidly invasive pulmonary infection subject to immune status and general debilitation.
Depending upon host immune response, constitution, and the propensity of fungal invasion of parenchyma, clinical symptoms can be variable. A subset of patients may be asymptomatic with an incidental diagnosis of an aspergilloma.
However, hemoptysis is the most common clinical presentation reported anywhere between 54% to 87.5% in various case series.[rx][rx] It can turn into a massive fatal hemorrhage in 30% of patients. Interestingly, the size of mycetoma, the complexity of the lesion, the underlying predisposing lung disease, or prior minor hemoptysis cannot predict massive hemoptysis in aspergilloma.[rx][rx] Fever is rare, although constitutional symptoms of malaise, and weight loss may occur. If the organism invades the surrounding parenchyma, recurrent pneumonia, chronic cough, or pulmonary fibrosis can occur.[rx] Reports also exist of disseminated infections involving a more considerable extent of parenchyma, airway, or even other organs.
Extrapulmonary Asperigilloma
While fungal endocarditis accounts for less than 2% of all causes of endocarditis, aspergillus accounts for 20 to 25% of all cases of fungal endocarditis. Invasive aspergillus disease involving heart valves and chambers is even rarer.[rx][rx][rx]
There are case reports of aspergilloma of the heart almost uniquely in leukemia patients on chemotherapy or post stem cell transplant. They usually carry an ominous prognosis with death reported in all but one case within days to weeks of diagnosis. A transthoracic echocardiogram is a valuable diagnostic tool. Fungal vegetations on valves appear bulkier and more mobile and are prone to embolic complications, particularly in the brain. A combination of antifungal therapy with valve replacement is the recommended therapeutic approach. If a patient survives, lifelong antifungal treatment post-surgical valve replacement is advocated.
Central Nervous System Aspergilloma
Translocation of organisms through the vascular channels of nasal sinuses or pulmonary vasculature leads to single or multiple cerebral abscess formation. Additionally, aspergillus also tends to invade the intima of arteries and veins, causing necrotizing arteritis, thrombosis, and hemorrhage. The anterior and middle cerebral arterial distributions are most commonly involved.
In CNS aspergilloma, the initial presentation is with focal neurological deficits affecting the circulation territory involved. With progression, patients may have features of meningitis or symptoms of raised intracranial pressure. Rarely intra-aortic thrombosis leads to mycotic aneurysms where clinical manifestations are similar to acute subarachnoid hemorrhage. Common presenting symptoms are acute or subacute headache, vomiting, hemiparesis, cranial nerve deficits, convulsions, and sensory impairment of varying degrees. Patients are often afebrile or have a low-grade fever, and the disease may have an indolent course over months.[rx][rx]
In a relevant clinical setting, characteristic CT chest findings combined with a microbial presence on sputum culture and serological evidence (serum antibodies) clinches the diagnosis.
The European Society for Clinical Microbiology and Infectious Diseases, in collaboration with the European Respiratory Society, has published the most comprehensive guideline for the diagnosis and management of chronic pulmonary aspergillosis, including aspergilloma. Consistent radiological findings, in association with serological and microbiological evidence of Aspergillus species in an individual, with symptoms lasting over three months satisfy the criteria for diagnosis after excluding other differentials with certainty.
A chest X-ray is often the first diagnostic test ordered in a patient presenting with symptoms. It shows upper lobe predominant cavitation, thickening, scarring, and occasionally a rounded mass-like opacity within the cavity.
CT scan provides more delineation and has some characteristic findings
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The appearance of a solid spherical lesion within the cavitary space
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Halo sign of surrounding inflammatory reaction around the cavity wall
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Air crescent sign separating the fungus ball from the wall in the entirety or part of its circumference. (also present in lung abscess, hydatid cyst, and granulomatosis with polyangiitis)
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Monod sign is characterized by a change in position of the ball concerning the cavity, with a change in the position of the patient during imaging.
CT helps in defining the cavity wall thickness, architectural distortion and inflammation of surrounding parenchyma and pleura, the relationship of the mycetoma with surrounding blood vessels as well as the nature of neovascularization both in lung parenchyma and parietal pleura.
The upper lobe of either lung is the most common location, although the superior segment of the lower lobe can also be involved. Denning et al. have prescribed evidence of endobronchial aspergilloma in HIV patients as has been corroborated by later case reports even in immunocompetent patients or in association with inhaled foreign bodies.
Once imaging is suggestive, evidence of microbial presence, as well as immune response, is the next approach in the algorithm. Assay against galactomannan antigen – a polysaccharide component of the cell wall has high specificity. Usually, the sensitivity of galactomannan antigen is higher in bronchoalveolar lavage fluid than serum, although both tests are available commercially. False-positive are seen in patients concurrently on piperacillin-tazobactam, while false negatives can be seen with high-dose steroid therapy or with other non-fumigatus species of aspergillus.
IgG antibodies against Aspergillus species diagnosed by precipitin assay are positive in over 90% of cases. Aspergillus-specific IgE is also fairly elevated.
Confirmation of Aspergillus species in fungal stain, culture, or polymerase chain reaction, adds weight to the diagnosis but is not diagnostic by themselves because of poor diagnostic yield and low sensitivity as well as specificity. An isolated sputum culture can be negative in over 50% of cases. Occasionally biopsy and video thoracoscopy can also clinch the diagnosis.
On radiological diagnosis of a solitary brain abscess, which is more than 1.5 cm, stereotactic aspiration of contents helps in diagnosis, relief of mass effect, and improving the efficacy of antifungal therapy. Complete evacuation is, however, not recommended due to the risk of hemorrhage within the evacuated cavity.
CNS aspergilloma is also best confirmed by CT or MRI. Chronic abscess demonstrates ring and homogenous enhancement. Small cerebral abscesses not apparent on CT, can be picked up by increased sensitivity of MR imaging.
In general lumbar puncture is contraindicated due to the propensity of cerebral edema and, therefore, herniation and abscess rupture post puncture. Increased cellularity and CSF proteins with near-normal glucose levels are characteristic, although organisms are rarely found in CSF. The septate hyphae and conidia of Aspergillus species are best detected with Gomori Methenamine silver stain.
Immunoassay by double diffusion counter immunoelectrophoresis, immunofluorescence, and enzyme-linked immunosorbent assay can be helpful in diagnosis.
Treatment
Even though aspergillomas can often be diagnosed incidentally in an asymptomatic or minimally symptomatic patient, there is a significant risk of evolving complications. The natural history and risk of complications, therefore, become a deciding factor in choosing between surgical and conservative treatment options. Rafferty and colleagues noted that 20% of non-surgically treated mycetoma progresses to invasive aspergillosis. Similarly, Paneth et al. observed that after an episode of hemoptysis, 5-year survival for operated patients was 41% compared to 84% for conservatively treated patients. The treatment approach has, therefore, leaned towards surgical resection either preemptively on every patient diagnosed with aspergilloma, or in those with even one episode of hemoptysis, if the patient is a surgical candidate. Massard and colleagues advocated the prophylactic resection approach while Daly and colleagues preferred surgery only after hemoptysis.[rx][rx]
For patients with normal respiratory function, and with aspergilloma involving only one lung, 30-day postoperative mortality is anywhere between 1 to 5%. Antifungal therapy alone is, on the other hand, of limited benefit in treating either simple or complex aspergilloma.[rx][rx]
A significant proportion of patients with aspergilloma have a preexisting diseased lung. Therefore resection with lung-sparing surgery has been gaining ground over the years. While wedge resection can occasionally be an option for a small, simple mycetoma, anatomical resection of segments or lobes has been the favored approach. Evaluation of pleural space is done carefully to ensure the absence of fistula or residual infection. But at the same time, manipulation of the mycetoma itself is reduced to a minimum.
Pneumonectomy, although less favored can be a necessity in the following circumstances
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Intraoperative injury to major vessels like pulmonary artery
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Second stage pneumonectomy for lobar torsion
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Multiple unilateral complex mycetoma
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Significantly destroyed surrounding lung tissue
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Megamycetoma
Endo and colleagues performed pneumonectomies in 35% of their reported patients without any postoperative mortality.[rx]
Cavernostomy and cavernoplasty followed by muscle flap interposition was a practice in vogue until the late 1930s. It fell out of favor with increased morbidity and mortality compared to surgical resection. It has been slowly coming back in practice for a limited subgroup of patients who are not surgical candidates.[rx][rx]
For patients with pleural involvement with pleural aspergilloma, an open window thoracostomy or first stage thoracoplasty is performed, just as in chronic empyema. Certain centers will perform an intrathoracic muscle transposition in the same setting, thus obliterating the cavity.[rx]
These surgical procedures do have complications like shoulder deformity, restriction of mobility, chronic postoperative pain, and scoliosis that should be addressed with patients before surgery.
Major surgical complications include massive hemorrhage, bronchopleural fistula, empyema, and rarely lobar torsion. Pleural complications involve residual infection, empyema, incomplete reexpansion, and prolonged air leaks. A preexisting underlying lung disease like tuberculosis, emphysema, or fibrosis leads to loss of elasticity of the affected lung, thus preventing reexpansion. The incidence of all complications has been reported to be as high as 60%.[rx][rx] Surgical mortality in complex mycetomas ranges from 0% to 44%.
A local pulmonary or pleural recurrence often leads to a dramatic deteriorating clinical course. Even prophylactic adjuvant antifungal pharmacotherapy does not seem to reduce the risk of this adverse effect.[rx]
The source of postoperative bleeding can be aberrant systemic arteries, twisted bronchial vessels, or vascular adhesions due to chronic inflammation. Preoperative bronchial arterial embolization has been attempted in scenarios where there is a high risk of postoperative bleeding.[rx]
Passera and colleagues address some of the challenges of the surgery itself.[rx]
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Bronchovascular hilum can have induration with extra bronchial fibrosis and nodes affected by chronic infection. Routine taping of the main artery before dissection can help avoid bleeding complications.
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Extrapleural dissection reduces the risk of rupture of mycetoma in pleural space as well as the risk of bleeding.
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A bronchopleural fistula from bronchial deficiency can be an outcome of chronic inflammation, nonviable tissue, calcification, and atrophy. Coverage of the bronchial stump with pericardial, omental, or muscle flaps decreases the risk.
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Finally, the obliteration of the residual pleural cavity reduces the risk of empyema or residual infection in the pleural space not adequately filled by entrapment of the remaining lobes.
Although most fungi—and especially Aspergillus—fail to grow in healthy human tissue, significant growth may occur in people whose adaptive immune system is compromised, such as those with the chronic granulomatous disease, who are undergoing chemotherapy, or who have recently undergone a bone marrow transplantation. Within the lungs of such individuals, the fungal hyphae spread out as a spherical growth. With the restoration of normal defense mechanisms, neutrophils and lymphocytes are attracted to the edge of the spherical fungal growth where they lyse, releasing tissue-digesting enzymes as a normal function.
For inoperable patients, intracavitary instillation of antifungal agents through percutaneous or intrabronchial catheters can lead to short-term clinical improvement.[rx][rx]
Oakley and colleagues devised an algorithm for appropriate pre-surgical evaluation and risk stratification to improve outcomes. They divided patients into four categories
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CLASS 1 – fit individuals with no symptoms
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CLASS 2 – Fit individuals with severe symptoms
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CLASS 3 – Unfit individuals with no symptoms
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CLASS 4 – Unfit individuals with severe symptoms
Class 2 individuals were directed to surgical resection, while class 4 individuals were chosen for intracavitary installation or cavernostomy.
Surgical removal of aspergillus abscess, granuloma, and focally infarcted brain, coupled with systemic antifungal therapy, form the mainstay of management of CNS aspergillomas. When non-eloquent brain areas are involved, lobectomy for solitary Aspergillus fumigatus abscess is also an endorsed treatment option.
Some centers do prefer voriconazole extended therapy as an adjuvant treatment post-resection to control pleural contamination and encourage bronchial stump healing.[rx]
Postoperative survival has been reported to be similar in both simple and complex aspergilloma.[rx][rx]
Amphotericin B is the mainstay among pharmacological agents in brain aspergilloma. Liposomal amphotericin B is significantly less toxic than free amphotericin B. However, because of the poor CSF penetration of systemic forms, intracatheter installation into the abscess cavity has also been an advocated approach. A combination of 5-fluorocytosine 50-150 mg/kg orally every six hours with rifampin can have a synergistic benefit with amphotericin.[rx] The postoperative phase of patients with CNS aspergilloma demonstrates complications with remote intracerebral infarcts from the primary site of involvement. The use of steroids to control postoperative cerebral edema along with stress has been implicated as a cause of the dissemination of fungal hyphae to those remote vascular sites.[rx][rx]
Bronchial Arterial Embolization for Massive Hemoptysis
Bronchial arterial embolization is the favored approach for patients with massive hemoptysis both as a first-line treatment as well as a bridge to more definitive surgical resection. However, in advanced disease, architectural distortion, neovascularization, and multiple vascular sources often make identification and control a challenging task.
The source of hemoptysis is the bronchial circulation in 90% of cases, although various thoracic and abdominal branches of the aorta can provide collateral supplies to interstitium and bronchi rarely in 10% of cases. Identification and distinction from ectopic or orthotopic bronchial arteries can be challenging even on bronchial arteriograms. Bronchial arterial branches tend to follow a vertical or horizontal course before joining the bronchial tree, unlike non-bronchial collaterals who follow a transpleural course not following the bronchial tree.[rx]
In 70% of instances, bronchial arteries arise from the descending thoracic aorta in the T5-T6 segment, with variants arising from the aortic arch or ascending aorta and occasionally from other aortic branches in the thorax or abdomen. Importantly, in the same context, is the path of the anterior spinal artery receiving collaterals from up to eight segmental medullary arteries, ventral to lower thoracic and upper lumbar spinal cord.[rx][rx][rx]
Apart from supplying pulmonary interstitium and bronchi, bronchial arteries also provide blood flow to the visceral pleura, the middle third of the esophagus, vasa vasorum of the aorta, and pulmonary artery, and mediastinum.
Complications and adverse events are therefore related to nontarget embolization and transient vascular disruption in other mediastinal structures. Transient chest pain and dysphagia are the commonest reported adverse events and are usually self-limiting.[rx][rx]
Anterior spinal arterial embolization causing acute transverse myelitis is the most devastating outcome. However, it has been increasingly rare with advanced angiographic techniques, the use of microcatheters, and hypo or iso-osmolar contrast agents. Its rate of occurrence over the years has been reported between 1.4 to 6.5%.[rx][rx] Unintentional embolization of the occipital cortex through a fistula between a bronchial artery and pulmonary vein or vertebral arterial branch has been rarely reported, thus leading to cortical blindness.
Since adverse effects are rare, technical success occurs in greater than 90% of interventions with clinical success reported at 73 to 99% immediately post embolization. Unfortunately, recurrence is also frequent at 10 to 55% in studies up to a 4-year follow-up.[rx][rx][rx]
Complications
Hemoptysis is the most common presentation, as well as a complication of pulmonary aspergilloma. It can turn into a massive fatal hemorrhage in 30% of patients.
Chronic mycetoma can induce inflammation in the surrounding parenchyma, thus developing a variable extent of pulmonary fibrosis.
Among extrapulmonary manifestations, CNS aspergilloma can be dreadful in its varied presentations as intracerebral abscess, meningitis, intra-aortic thrombosis, mycotic aneurysm, and even subarachnoid hemorrhage.
Cardiac aspergilloma, as reported so far, is also almost universally fatal.
References
